Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.C(O)CCC.C(OC([N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)C)C.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH:29]1[CH:33]=[C:32]([C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:31]=[N:30]1
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 1000 mL round bottom flask was charged with 4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (10.00 g, 35.23 mmol), 1-butanol (25.0 mL), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15.66 g, 52.85 mmol), water (25.0 mL) and potassium carbonate (12.17 g, 88.08 mmol). This solution was degased 4 times, filling with nitrogen each time. To the solution was added tetrakis(triphenylphosphine)palladium(0) (4.071 g, 3.523 mmol). The solution was degased 4 times, filling with nitrogen each time. The mixture was stirred overnight at 100° C. After being cooled to room temperature, the mixture was filtered through a bed of celite and the celite was rinsed with ethyl acetate (42 mL). The filtrate was combined, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic extracts were combined and concentrated under vacuum with a bath temperature of 30-70° C. to give the final compound 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine. Yield: 78%. LC-MS: 316.2 (M+H)+.
Reaction SMILES: CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.[C:21]([O:25][C:26]([NH:28][C@@H:29]1[C:39]2[C:34](=[N:35][CH:36]=[CH:37][CH:38]=2)[C@@H:33]([CH2:40][C:41]([OH:43])=O)[CH2:32][CH2:31][C@H:30]1[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=1[F:51])=[O:27])([CH3:24])([CH3:23])[CH3:22].[NH:52]1[CH2:57][CH2:56][CH:55]([N:58]2[C:66]3[C:61](=[N:62][CH:63]=[CH:64][CH:65]=3)[NH:60][C:59]2=[O:67])[CH2:54][CH2:53]1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C)C=O>[F:51][C:45]1[C:46]([F:50])=[CH:47][CH:48]=[CH:49][C:44]=1[C@@H:30]1[CH2:31][CH2:32][C@H:33]([CH2:40][C:41](=[O:43])[N:52]2[CH2:53][CH2:54][CH:55]([N:58]3[C:66]4[C:61](=[N:62][CH:63]=[CH:64][CH:65]=4)[NH:60][C:59]3=[O:67])[CH2:56][CH2:57]2)[C:34]2=[N:35][CH:36]=[CH:37][CH:38]=[C:39]2[C@H:29]1[NH:28][C:26](=[O:27])[O:25][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@@H](CC(=O)O)CC[C@H]1c1cccc(F)c1F
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@@H](CC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Reaction time: 0.33 h
Yield: 89.5 %

Procedure:
DEPBT (0.115 g, 0.384 mmol) was added to a dimethylformamide (4 mL) solution of 2-((5S,6S,9R)-5-(tert-butoxycarbonylamino)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetic acid (0.111 g, 0.256 mmol), 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.084 g, 0.384 mmol) at room temperature. After stirring for 20 min, triethylamine (0.054 mL, 0.384 mmol) was added to the reaction mixture. The reaction was stirred overnight at room temperature. The reaction was diluted with ethyl acetate and washed three times with water. The ethyl acetate layer was separated, dried (sodium sulfate), filtered and concentrated. Flash chromatography using methanol in methylene chloride from 0 to 10% gave the desired product (145 mg, 90%):
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].N[C@H](C(O)=O)[CH2:11][C:12]1[CH:21]=C2C(C=CC=C2)=C[CH:13]=1.[OH-].[K+].Br[CH2:28][CH:29]([CH3:31])[CH3:30]>C(O)C>[CH3:11][CH:12]([CH3:21])[CH2:13][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: Oc1ccccc1O
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CC(C)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)COc1ccccc1OCC(C)C

Procedure:
Catechol (220.22 g, 2 mol) and Nal (10.49 g, 0.14 mol) were initially charged in 900 ml of ethanol and heated to reflux. Subsequently, KOH (56.11 g, 1 mol) dissolved in about 300 ml of ethanol and, simultaneously, 1-bromo-2-methylpropane (137.03 g, 1 mol, 108.75 ml) were slowly added dropwise. The mixture was refluxed further overnight. On the next day, the same amounts of KOH and alkyl bromide were again added. This procedure was repeated a total of seven times. After cooling the reaction mixture, the solution was decanted from the solid. The filter cake was washed with ethanol. The organic phase was evaporated. The filter cake was dissolved in 1 l of warm water and admixed with the organic phase which had been diluted with ethyl acetate. After phase separation, the organic phase was again stirred with 10% strength aqueous NaOH, washed with water and dried over Na2SO4. The crude product obtained after taking off the solvent was fractionally distilled under reduced pressure.
Reaction SMILES: [Cl-].[C:2]([C:5]1[CH:13]=[CH:12][C:11]2[C:7](=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]3[CH2:16][CH2:15][CH2:14][N+:10]3=2)[CH:6]=1)(O)=[O:3].S(Cl)([Cl:25])=O.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(Cl)(Cl)Cl>[Cl-:25].[O:30]1[CH2:31][CH2:32][N:27]([C:2]([C:5]2[CH:13]=[CH:12][C:11]3[C:7](=[C:8]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:9]4[CH2:16][CH2:15][CH2:14][N+:10]4=3)[CH:6]=2)=[O:3])[CH2:28][CH2:29]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc2c(c1)c(-c1ccccc1)n1[n+]2CCC1
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc2c(c1)c(-c1ccccc1)n1[n+]2CCC1)N1CCOCC1
Temperature: 50 °C

Procedure:
The mixture of 2 g of 2,3-dihydro-7-carboxy-9-phenyl-1H-pyrazolo[1,2-a]indazolium chloride and 30 ml of thionyl chloride was heated at 50° C. for 30 minutes with stirring, and the resulting reaction mixture was concentrated to produce residue. The mixture of the above residue, 50 ml of chloroform and 5 ml of morpholine was stirred at room temperature for 30 minutes, and then the mixture was filtered. The filtrate was concentrated to produce an oily product, which was purified by column chromatography on HP-2MG® (Mitsubishi Chemical Industries Limited) using water as an eluent to produce 1.5 g of 2,3-dihydro-7-morpholino carbonyl-9-phenyl-1H-pyrazolo[1,2-a]indazolium chloride as an oily substance.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[C-:10]#[N:11].[Na+].O.C(OCC)(=O)C>CS(C)=O>[C:10]([CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:11]
Reactant: [C-]#N
Reactant: Cc1ncccc1CCl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1ncccc1CC#N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
The mixture of 3-chloromethyl-2-methylpyridine (9.2 g) and sodium cyanide (9.55 g) in dimethyl sulfoxide (80 ml) was stirred for 30 minutes at 80° C. The reaction mixture was poured into a mixture of water (200 ml) and ethyl acetate (1 l). Organic layer was separated, washed with brine and dried over magnesium sulfate. Concentration of the solvent gave a residue, which was chromatographed on silica gel (300 ml) eluting with a mixture of hexane and ethyl acetate (1:4, V/V) to give 3-cyanomethyl-2-methylpyridine (7.6 g).
Reaction SMILES: [NH2:1][C:2]([CH:4]1[O:18][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH2:5]1)[NH:12][C:11](=[O:17])[CH2:10][CH2:9]3)=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[C:2]([CH:4]1[O:18][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH2:5]1)[NH:12][C:11](=[O:17])[CH2:10][CH2:9]3)#[N:1]
Reactant: Cc1cc2c(c3c1NC(=O)CC3)OC(C(N)=O)C2
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(C#N)C2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.5 %

Procedure:
The compound obtained in Example 259 (0.47 g, 1.9 mmol) was dissolved in methylene chloride (40 ml) and pyridine (0.64 ml, 8 mmol). To the obtained solution, trifluoroacetic anhydride (0.56 ml, 4 mmol) was added dropwise while cooling in an ice--water bath, and the mixture was stirred at 0° C. for 1.5 hours. Pyridine (0.64 ml, 8 mmol) and trifluoroacetic anhydride (0.56 ml, 4 mmol) were further added, and stirring was continued at 0° C. for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure. To the resultant residue, saturated ammonia--methanol (30 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure. The residue was combined with chloroform, and extracted. The organic phase was washed with water, aqueous 5% potassium hydrogensulfate, saturated aqueous sodium bicarbonate solution, and saturated aqueous NaCl solution in this order, and dries over magnesium sulfate. The solvent was reduced under reduced pressure, and the residue was subjected to silica gel column chromatography for separation and purification. As a result, 0.41 g of the title compound was obtained as pale yellow powder (94%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]=[CH:2]2.ClS([N:12]=[C:13]=[O:14])(=O)=O.S([O-])([O-])=O.[Na+].[Na+].O.[OH-].[Na+]>C(Cl)Cl>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]1[CH:2]2[NH:12][C:13]1=[O:14]
Reactant: C1=CC2C=CC1C2
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C1NC2C3C=CC(C3)C12
Temperature: -5 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
In a 500 mL RBF, fit with dropping funnel and stir bar, under N2 was charged with Methylene chloride (100 mL) and 2,5-Norbornadiene (25 mL, 0.24 mol). The mixture was cooled in an ice/NaCl bath (ca. −5° C.). The dropping funnel was charged with Chlorosulfonyl Isocyanate (21.4 mL, 0.246 mol) and Methylene chloride and this mixture was added dropwise slowly to the reaction over about 1 hour. The mixture was held at −5° C. for about 1 hour further with stirring then warmed to room temp by removal of the ice bath. This warming occurred over about 2 h. The mixture was quenched with water (60 mL) and stirred for 10 min. The org layer was separated, washed with brine, dried (sodium sulfate) and concentrated to give a pale yellow oil. The pale yellow oil was dissolved in Methylene chloride (100 mL, 2 mol) and added dropwise to a −5° C. (Ice/NaCl bath) solution of Sodium sulfite (24.5 g, 0.194 mol), Methylene chloride (30 mL, 0.5 mol), and Water (70 mL, 4 mol) in a two neck 500 mL RBF. During the addition, the pH of the mixture was kept between 7 and 10 (monitor by pH paper) by addition of 10% NaOH. The addition took about 1 h. Following the complete addition, the pH was adjusted to 8.5 and the milky white solution was stirred for 1 h at −5° C. The mixture was diluted with about 400 mL of methylene chloride and the mixture stirred vigorously overnight. The stirred mixture was transferred to a 1 L separatory funnel and the layers separated. The aq was extracted 2× further with dichloromethane (200 mL each) and the combined organics washed with brine, dried (MgSO4), filtered through a bed of Celite and concentrated to give 3-Aza-tricyclo[4.2.1.0(2,5)]non-7-en-4-one a white solid. (21.6 g) (65% yield); MP: 94-97° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CO.ClCCl>[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[C:14]1[O:10][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[N:1]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: COc1ccc(O)c(N)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2oc(-c3ccc(Cl)cc3Cl)nc2c1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-4-methoxyphenol (1 g, 7.1 mmol), a compound of formula (d) in 20 mL MeOH was added 2,4-dichlorobenzaldehyde (1.2 g, 7.1 mmol), a compound of formula (e). The mixture was heated at 45° C. for 12 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in 50 mL dichloromethane. To the solution was added DDQ (1.7 g, 7.8 mmol), and the mixture was allowed to stir at room temperature for 30 minutes. The reaction mixture was then diluted with an additional 30 mL of dichloromethane and washed sequentially with saturated NaHCO3 (2×50 mL) and brine. The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure to yield 2-(2,4-dichlorophenyl)-5-methoxybenzoxazole, a compound of formula (f), which was purified using flash column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH2:15])[CH:6]=[C:7]([O:12][CH3:13])[C:8]=1[CH:9]([CH3:11])[CH3:10].Br[C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=1[F:25]>>[CH3:13][O:12][C:7]1[CH:6]=[C:5]([CH:14]=[CH:15][C:21]2[C:22]([F:23])=[CH:17][C:18]([F:25])=[CH:19][C:20]=2[F:24])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[CH:9]([CH3:11])[CH3:10]
Reactant: Fc1cc(F)c(Br)c(F)c1
Reactant: C=Cc1cc(OC)c(C(C)C)c(OC)c1
Product: COc1cc(C=Cc2c(F)cc(F)cc2F)cc(OC)c1C(C)C
Yield: 58 %

Procedure:
This compound was synthesized from (3,5-dimethoxy-4-i-propylphenyl)ethene and 1-bromo-2,4,6-triflurobenzene in 58% yield in the same procedure as described in preparation of 31B. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.0 Hz, 6H), 3.62 (qint, J=7.1 Hz, 1H), 3.89 (s, 6H), 6.73 (s, 2H), 6.79-7.55 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26](=[O:45])[CH2:27][C@@H:28]([O:43][CH3:44])[C@@H:29]([N:34]([CH3:42])[C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].C1C2C(COC([NH:63][C@:64]([C:69](O)=[O:70])([CH3:68])[CH:65]([CH3:67])[CH3:66])=O)C3C(=CC=CC=3)C=2C=CC=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCC)C>ClCCl>[CH3:66][CH:65]([CH3:67])[C@@:64]([C:69]([NH:37][C@H:36]([C:35]([N:34]([C@@H:29]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@H:28]([O:43][CH3:44])[CH2:27][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[C:5]([NH:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:6])=[O:45])[CH3:42])=[O:41])[CH:38]([CH3:39])[CH3:40])=[O:70])([CH3:68])[NH2:63]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC(C)[C@@](C)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCNCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)[C@](C)(N)C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.8 %

Procedure:
A solution of #114 (224 mg, 0.354 mmol, 1.0 eq.) in 2 mL of dichloromethane was added to a solution of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-methyl-L-isovaline (125 mg, 0.354 mmol, 1.0 eq.) in 4 mL of dichloromethane. Hunig's base (0.187 mL, 1.06 mmol, 3.0 eq.) was added followed by HATU (167 mg, 0.425 mmol, 1.2 eq.). The reaction was allowed to stir at room temperature for 12 hours. The reaction was concentrated in vacuo and then taken up in ethyl acetate before being washed two times with 1M HCl and once with brine. The organic layer was dried over sodium sulfate and decanted. The organic solvent was removed in a genevac. THF (4 mL) was added followed diethylamine (2 mL, 19 mmol, 53.7 eq.). The reaction was allowed to stir for ˜12 hours. Reaction was concentrated using a genevac followed by silica chromatography (Gradient: 0%-30% methanol in ethyl acetate) producing #147 (216 mg, 82%) as a solid. LC-MS (Protocol Q): m/z 746.6 [M+H+] retention time=1.29 minutes. 1H NMR (400 MHz, DMSO-d6), δ 8.56 (m), 8.31-8.39 (m), 8.50 (d), 8.30 (br d), 7.87-8.01 (m), 7.80 (d), 7.40-7.53 (m), 7.14-7.30 (m), 4.45-4.78 (m), 3.94-4.04 (m), 3.70-3.79 (m), 3.61-3.69 (m), 3.42-3.59 (m), 2.97-3.37 (m), 2.80-2.92 (m), 2.32-2.49 (m), 2.05-2.30 (m), 1.61-1.89 (m), 1.37-1.56 (m), 1.14-1.135 (m), 0.70-1.11 (m).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C@H:3]([OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:13]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C1C=CC=CN=1)C.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl.O.C(N(CC)CC)C>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:10][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:2]([F:11])([F:12])[F:1])=[O:26])=[CH:28][CH:29]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCC[C@@H](O)C(F)(F)F
Agent: CN(C)c1ccccn1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Yield: 50.9 %

Procedure:
After 3.7 g of (R)-(+)-1,1,1-trifluoro-2-octanol and 1.2 g of triethylamine were added to 40 ml of methylene chloride to form a mixture, 40 ml of methylene chloride solution containing 4.3 g of 4-benzyloxybenzoic acid chloride was dropped with stirring to the mixture. Further, 0.5 g of dimethylaminopyridine was added and the mixture thus formed was stirred at an ambient temperature for a whole day and night. Thereafter, the reaction liquid was poured in a water tank to make it neutral. After the methylene chloride layer thus formed was extracted, the reaction liquid was dehydrated with an anhydrous magnesium sulfate. After the solvent was distilled off, the reaction product thus formed was subjected to separation and purification by a silica gel column chromatography to obtain 3.5 g of the objective compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH:15][C:14]([C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[O:16])=[CH:22][CH:21]=1
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: O=Cc1ccc(O)cc1
Product: O=C(C=Cc1ccc(O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
3-(4-Hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is purified by silica-gel chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([S:10]([C:13]([CH3:21])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])(=[O:12])=[O:11])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([CH2:33][OH:34])=[CH:29][C:30]([O:31][CH3:32])=[C:25]2[NH:24][C:23]1=[O:35].CN(C)C=[O:39]>C(OCC)(=O)C.[O-2].[Mn+4].[O-2]>[C:33]([C:28]1[N:27]=[C:26]2[N:22]([C:3]3[CH:4]=[C:5]([S:10]([C:13]([CH3:21])([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH3:14])(=[O:12])=[O:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=3[Cl:1])[C:23](=[O:35])[NH:24][C:25]2=[C:30]([O:31][CH3:32])[CH:29]=1)([OH:39])=[O:34]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)cc(CO)nc32)cc1S(=O)(=O)C(C)(C)c1ccccc1
Reactant: CN(C)C=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)cc(C(=O)O)nc32)cc1S(=O)(=O)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[2-chloro-4-methoxy-5-(1-methyl-1-phenylethylsulfonyl)-phenyl]-5-hydroxymethyl-7-methoxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (40 mg) in N,N-dimethylformamide (2 mL) was added manganese(IV) oxide (0.4 g), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with ethyl acetate, and the insoluble material was removed by filtration. The filtrate was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue were added tert-butanol (1.5 mL), water (0.15 mL), sodium dihydrogen phosphate dihydrate (10 mg), 2-methyl-2-butene (18 mg) and a solution of sodium chlorite (20 mg) in water (0.3 mL) successively, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture were added 1 mol/L hydrochloric acid and water, and the precipitated crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give the title compound (19 mg).
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH2:4]([O:6][C:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19]Br)[CH:17]=2)[C@H:12]([N:23]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:11][C@@H:10]1[CH3:43])=[O:8])[CH3:5].O>CN(C)C=O>[CH2:4]([O:6][C:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19][S:2][CH3:1])[CH:17]=2)[C@H:12]([N:23]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:11][C@@H:10]1[CH3:43])=[O:8])[CH3:5]
Reactant: C[S-]
Reactant: CCOC(=O)N1c2cc(CBr)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2cc(CSC)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reaction time: 6 h
Yield: 42.1 %

Procedure:
To a suspension of sodium thiomethoxide (11 mg, 0.156 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-bromomethyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 90) (100 mg, 0.156 mmol), and the reaction was stirred for 6 h. The reaction mixture was then poured into water and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The excess N,N-dimethylformamide was azeotroped off with heptanes. Purification by silica gel chromatography using 10-15% ethyl acetate/hexanes as eluent afforded the title product (0.040 g, 42%): 1H NMR (CDCl3) δ 1.1 (d, 3H), 2.1 (s, 3H), 3.8 (m, 6H), 6.4 (s, 1H), 7.3 (s, 1H), 7.7 (s, 2H), 7.8 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=S)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1CCC([N:40]=[C:41]=[N:42]C2CCCCC2)CC1.C(N(CC)C(C)C)(C)C.N#CN>C(#N)C>[C:41]([N:42]=[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)[NH:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:40]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1ccc(NC(=S)N2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)cc1OC
Agent: N#CN
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=NC#N)N2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)cc1OC
Yield: 32.7 %

Procedure:
To an acetonitrile solution (15 mL) of N-(3,4-dimethoxyphenyl)-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinethiocarboxamide (499 mg, 1.07 mmol) described in WO 98/14431, DCC (4397 mg, 2.13 mmol), N,N-diisopropylethylamine (Hünig base) (0.19 mL, 1.09 mmol) and cyanamide (224 mg, 5.32 mmol) were added, followed by heating under reflux in argon atmosphere for 2 days. DCC (439 mg, 2.13 mmol), Hünig base (0.19 mL, 1.09 mmol) and cyanamide (224 mg, 5.32 mmol) were further added thereto, followed by heating under reflux for 2 days. After the reaction solution was concentrated, the resulting residue was purified by silica gel column chromatography to give the target compound (167 mg, 0.35 mmol).